Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints, which may lead to structural damage of the cartilage and bone. The receptor activator of nuclear factor B ligand (RANKL) has been shown to play a pivotal role in inflammatory joint diseases. Its functions in bone destruction and immune responses make RANKL an important target for future RA therapies. Our preliminary data showed that RANKL genetic polymorphisms were associated with younger age of the disease onset in rheumatoid factor positive (RF+) Caucasian RA patients. This association was confirmed in RF+ African-American RA patients. The proportion of RF+ African-American patients carrying 2 copies of the RANKL risk haplotype was highest (33%) in those who developed RA during the third decade, with a declining trend among those who developed RA during their fourth (20%), fifth (6%), sixth (9%), and later (0%) decades (p = 0.004 for the age-related declining trend). This declining trend of proportion in age of RA onset was also evident in anti-CCP+ African- American patients (p = 0.0006) and RF+ Caucasian patients (p = 0.03). A significantly increasing trend of the RANKL risk haplotype was observed in normal Caucasian controls (10%), RF+ Caucasian RA patients (17%), and RF+ polyarticular juvenile idiopathic arthritis (JIA) Caucasian patients (26%) (p = 0.002). Our results showed significant association of novel RANKL polymorphisms with an earlier age at RA onset in two distinct ethnic groups. These results also suggested genetic differences between patients with early-onset and those with late-onset RA. We propose to 1) fine-map the RANKL gene to identify boundaries of haplotype block(s) associated with younger age of RA onset in both Caucasian and African-American RF+ RA patients, 2) assess potential functional polymorphisms within RA-associated haplotype block(s) to localize RANKL causal variant(s). Results from this study may identify biomarkers for who is at greatest risk for early RA and may shed new insights of molecular mechanisms leading to early development of RA, which may have implications for therapeutic interventions in the future. This study aims to identify genetic polymorphisms and to understand potential molecular mechanisms that predispose to early development of rheumatoid arthritis (RA). Results from this study are likely to provide information on the identification of individuals at high risk for RA at young ages, which may allow early therapeutic interventions to prevent bone erosions. The understanding of molecular mechanisms for the pathogenesis of RA may lead to the development of novel targeted medications. [unreadable] [unreadable] [unreadable]